Midazolam as a potential CYP3A phenotyping probe for cabazitaxel metabolism.

Cabazitaxel is a novel taxane approved for treatment in men with metastasized
hormone refractory prostate cancer (MHRPC). Although its dosing is
individualized on body surface area (BSA), variability in cabazitaxel exposure
explains variability in toxicity.
Cabazitaxel is mainly metabolized by the cytochrome P450 isoenzyme 3A (CYP3A).
In cancer patients, CYP3A activity may vary a 4-fold and it is known that BSA
does not account for all variability in clearance. Furthermore, in obese and
underweight patients BSA is a poor predictor of clearance.
Midazolam is also metabolized by CYP3A and a commonly used CYP3A phenotyping
probe for prediction of clearance of other CYP3A substrates. Therefore,
clearance of midazolam might be a good predictor for clearance, and thus
exposure, of cabazitaxel. This relationship may guide future cabazitaxel
dosing individualization studies based on CYP3A phenotyping to optimize
treatment and reduce unwanted toxicity.

The primary objective of this study is to investigate whether CYP3A phenotype,
as measured with midazolam clearance, correlates with cabazitaxel clearance.
Our secondary objective is to investigate whether this CYP3A phenotype
outperforms BSA as a predictor of clearance.

Prospective observational cohort study

All men will be administered a single intravenous dose of midazolam (2.5mg)
before regular treatment with cabazitaxel. After midazolam and after
cabazitaxel administration blood samples will be collected for determination of
their pharmacokinetics.

The nature and extent of the burden associated with participation are
considered to be minimal, since the only extra interventions outside of routine
clinical care are administration of midazolam and collection of blood samples.
There is no individual benefit to be expected from participation.